Quinuclidine derivatives

ABSTRACT

Quinine, quinidine and analogs thereof, are prepared by reacting a 4-quinolyllithium compound with a 4,5-erythro-5-ethyl(or vinyl)-quinuclidine-2 ξ-carboxaldehyde or the corresponding quinuclidine-2-carboxylic acid alkyl ester. Also described, inter alia, is the preparation of a 4,5-erythro-5-ethyl(or vinyl)-quinuclidine-2 ξ-carboxaldehyde, and a 4,5-erythro-5-ethyl(or vinyl)-quinuclidine-2 ξ-carboxylic acid and esters thereof. The end products are useful as anti-malarial and antiarrhythmic agents.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a division of U.S. Pat. application Ser. No.166,583, filed July 27, 1971, now U.S. Pat. No. 3,823,146, which in turnis a continuation-in-part of U.S. Pat. application Ser. No. 117,131,filed Feb. 19, 1971, now abandoned, which in turn is acontinuation-in-part of U.S. Pat. application Ser. No. 20,034, filedMar. 16, 1970, now abandoned.

BRIEF SUMMARY OF THE INVENTION

The invention relates to the preparation of compounds of the formulas Iand II ##SPC1##

enantiomers and racemates thereof;

Wherein m is 1 or 2; R₁ is hydrogen, hydroxy, halogen, trifluoromethyl,lower alkyl, lower alkoxy, or when m is 2, with an adjacent R₁, is alsomethylenedioxy; and R₂ is ethyl or vinyl.

In one aspect, the invention relates to the preparation of compounds offormulas I and II, wherein R₂ is ethyl or vinyl, by a process whichcomprises reacting the mixture of epimeric 5(R)-ethyl(orvinyl)-4(S)-quinuclidine-2ξ-carboxaldehydes, enantiomers or racemates,with a 4-quinolyllithium compound.

In another aspect, the invention relates to the preparation of compoundsof formulas I and II, wherein R₂ is ethyl or vinyl, by a process whichcomprises reacting the mixture of epimeric 5(R)-ethyl(orvinyl)-4(S)-quinuclidine-2ξ-carboxylic acid alkyl esters, enantiomers orracemates thereof, with a 4-quinolyllithium compound and thereafterreducing the resulting 4-[5(R)-ethyl(or vinyl)-4(S)-quinuclidin-2(R orS)ylcarbonyl]quinoline, its enantiomer or its racemate, to thecorresponding end product of formulas I and II.

In still another aspect, the invention relates to intermediates of theformulas: ##SPC2##

Their racemates and enantiomers,

Wherein R₂ is as previously described, R₃ is lower alkyl, aryl oraryl-lower alkyl; m is 1 or 2, and R'₁ is hydroxy, halogen,trifluoromethyl, lower alkyl or lower alkoxy, or when m is 2, with anadjacent R₁, is also methylenedioxy.

DETAILED DESCRIPTION OF THE INVENTION

The term "lower alkyl" as used herein denotes a hydrocarbon groupcontaining 1-7 carbon atoms, such as methyl, ethyl, propyl, butyl andthe like; methyl and ethyl are preferred. The term "lower alkoxy"denotes a lower alkyl ether group in which the lower alkyl moiety is asdescribed above. The term "halogen" denotes all the halogens, i.e.,bromine, chlorine, fluorine and iodine; chlorine is preferred. The term"aryl" denotes phenyl or phenyl bearing one or more substituentsselected from the group consisting of halogen, trifluoromethyl, loweralkyl, lower alkoxy, nitro, amino, lower alkylamino and di-loweralkylamino. Exemplary of "aryl-lower alkyl" are benzyl, phenethyl andthe like.

A process aspect of the invention is exemplified by Reaction Scheme Ia.

Scheme Ia ##SPC3##

wherein R₃ is lower alkyl, aryl or aryl-lower alkyl.

In Reaction Scheme Ia, the racemic1,1,1-trichloro-3-(3-ethyl-4-pyridinyl)propan-2-ol of formula III [alsoknown as 3-ethyl-4-(2-hydroxy-3,3,3-trichloropropyl)pyridines] or eitherof its enantiomers is converted to the mixture of racemic, epimeric cis1,1-dichloro-3-(3-ethyl-4-piperidinyl)propan-2ξ-ols of formulas IVa andVa or their corresponding enantiomers utilizing a hydrogenationcatalyst, for example, a noble metal, such as palladium, platinum andrhodium; Raney nickel; and the like. The hydrogenation is convenientlycarried out at room temperature or above room temperature, preferably at60° and at a hydrogen pressure of about 1 atmosphere to about 100atmospheres. Moreover, the hydrogenation can be suitably carried out inthe presence of water and an inert organic solvent, for example, analkanol, such as ethanol, methanol and the like, and in the presence ofa mineral acid, such as hydrochloric, hydrobromic, sulfuric acid and thelike, or an organic acid, such as acetic acid, tartaric acid and thelike.

The enantiomers or racemates of epimeric cis1,1-dichloro-3-(3-ethyl-4-piperidinyl)propan-2ξ-ols of formulas IVa andVa are converted to the mixture of epimeric5(R)-ethyl-4(S)-quinuclidine-2ξ-carboxaldehydes of formula VIa,enantiomers or racemates, utilizing a cyclizing and dehydrochlorinatingagent. Exemplary of such agents are bases, for example, alkali metalhydroxides, such as sodium hydroxide and potassium hydroxide; alkalimetal alkoxides, such as potassium t-butoxide; and basic anion exchangeresins, such as Amberlite anion exchange resin IRA-401 (OH) and thelike. The reaction is conveniently carried out at room temperature;however, higher or lower temperatures may also be utilized. Moreover,the reaction can be suitably carried out in the presence of an inertorganic solvent, for example, an alkanol, such as methanol, ethanol andthe like; a hydrocarbon, such as benzene, toluene, hexane, petroleumether and the like; or an ether, such as tetrahydrofuran, diethylether,dioxane and diglyme; or a mixture of water and an immiscible inertorganic solvent, such as benzene, dichloromethane or the like.

The mixture of epimeric 5(R)-ethyl-4(S)-quinuclidine-2ξ-carboxyaldehydesof formula VIa, enantiomers or racemates, is converted to the mixture ofepimeric 5(R)-ethyl-4(S)-quinuclidine-2ξ-carboxylic acids of formulaVIIa, enantiomers or racemates, utilizing an oxidizing agent. As theoxidizing agent, there can be utilized silver oxide, chromic acid,potassium permanganate, and the like. The oxidation is convenientlycarried out at room temperature or below, and if desired, in thepresence of a solvent such as an alkanol or water.

The mixture of epimeric 5(R)-ethyl-4(S)-quinuclidine-2ξ-carboxylic acidsof formula VIIa, enantiomers or racemates, is converted to the mixtureof epimeric 5(R)-ethyl-4(S)-quinuclidine-2ξ-carboxylic acid alkyl estersof formula VIIIa, enantiomers or racemates, utilizing an esterifyingagent. As the esterifying agent, there can be utilized alkanols such asethanol, methanol, and the like, in the presence of an acid such ashydrogen chloride, sulfuric acid and the like. The esterification isconveniently carried out at a temperature in the range of between aboutroom temperature and the boiling temperature of the reaction mixture.

Still another process of the invention is exemplified by Reaction SchemeIb:

Scheme Ib ##SPC4##

wherein R₂ and R₃ are as previously described.

In Reaction Scheme Ib the N-benzoyl-3(R)-ethyl(orvinyl)-4(S)-piperidineacetaldehyde of formula IX, its enantiomer orracemate, is converted to the corresponding mixture of epimeric1,1-dichloro-3-[3(R)-ethyl(or vinyl)-4(S)-piperidinyl]propan-2ξ-ols offormulas IV and V, enantiomers or racemates, utilizing a Grignardreagent, such as dichloromethyllithium. The reaction is convenientlycarried out at room temperature and below room temperature, preferablybetween about 0° and about -70°C. Moreover, the reaction can be suitablycarried out in the presence of an inert organic solvent, for example, anether, such as tetrahydrofuran, diethylether, dioxane and diglyme; or ahydrocarbon such as benzene, toluene, hexane, petroleum ether and thelike.

The mixture of epimeric 1,1-dichloro-3-[3(R)-ethyl(orvinyl)-4(S)-piperidinyl]propan-2ξ-ols of formulas IV and V, enantiomersor racemates, are converted to the mixture of epimeric 5(R)-ethyl(orvinyl)-4(S)-quinuclidine-2ξ-carboxaldehydes of formula VI, enantiomersor racemates, by the procedure previously described for the compounds offormulas IVa and Va.

The mixture of epimeric 5(R)-ethyl(orvinyl)-4(S)-quinuclidine-2ξ-carboxaldehydes of formula VI, enantiomersor racemates, is converted to the mixture of epimeric 5(R)-ethyl(orvinyl)-4(S)-quinuclidine-2ξ-carboxylic acids of formula VII, enantiomersor racemates, by the procedure previously described for the compound offormula VIa.

The mixture of epimeric 5(R)-ethyl(orvinyl)-4(S)-quinuclidine-2ξ-carboxylic acids of formula VII, enantiomersor racemates thereof, is converted to the mixture of epimeric5(R)-ethyl(or vinyl)-4(S)-quinuclidine-2ξ-carboxylic acid alkyl estersof formula VIII, enantiomers or racemates thereof, by the procedurepreviously described for the compound of formula VIIa.

A further process aspect of the invention is exemplified by ReactionScheme II:

Scheme II ##SPC5##

enantiomers and racemates thereof,

wherein R₁, R₂ and m are as previously described.

In Reaction Scheme II, the mixture of epimeric 5(R)-ethyl (orvinyl)-4(S)-quinuclidine-2ξ-carboxaldehydes of formula VI, enantiomersor racemates thereof, is reacted with a 4-quinolyllithium compound offormula X to yield the corresponding α(S)-[5(R)-ethyl(orvinyl)-4(S)-quinuclidin-2(R)-yl]-4-quinoline-methanol of formula I,enantiomer or racemate thereof, and α(R)-[5(R)-ethyl(orvinyl)-4(S)-quinuclidin-2(S)-yl]-4-quinolinemethanol of formula II,enantiomer or racemate thereof. The 4-quinolyllithium compound offormula X is reacted in equimolar or greater than equimolar proportionswith the compound of formula VI. Preferably, two molar proportions ofthe quinolyllithium compound are utilized. The reaction is convenientlycarried out at room temperature or below room temperature, preferably ata temperature in the range of between about 0° and about -70°, in thepresence of an inert organic solvent, for example, an ether, such asdiethylether, tetrahydrofuran, dioxane and diglyme; or a hydrocarbon,such as benzene, toluene and the like. The reaction is convenientlycarried out in the presence of complexing agents such as1,4-diazabicyclo[2.2.2] octane or tetramethylethylenediamine.

Representative of the compounds of formula X are the following:

4-quinolyllithium;

6-methoxy-4-quinolyllithium;

6-methyl-4-quinolyllithium;

7-methoxy-4-quinolyllithium;

6,7-dimethoxy-4-quinolyllithium;

6,7-methylenedioxy-4-quinolylithium;

6,8-dimethoxy-4-quinolyllithium;

6-chloro-4-quinolyllithium;

7-trifluoromethyl-4-quinolyllithium;

7-chloro-4-quinolyllithium;

6,8-dichloro-4-quinolyllithium; and the like.

Since the foregoing 4-quinolyllithium compounds are highly labile, it ispreferred to prepare them in situ, by reacting the corresponding4-bromoquinoline with, for example, n-butyllithium in the presence of asolvent, for example, a hydrocarbon, such as benzene, toluene, hexane,petroleum ether; or an ether, such as dioxane, ether, diglyme,tetrahydrofuran and the like. Exemplary of the 4-bromoquinolinecompounds are:

4-bromoquinoline;

4-bromo-6-methoxyquinoline;

4-bromo-6-methylquinoline;

4-bromo-7-methoxyquinoline;

4-bromo-6,7-dimethoxyquinoline;

4-bromo-6,7-methylenedioxyquinoline;

4-bromo-6,8-dimethoxyquinoline;

4-bromo-6-chloroquinoline;

4-bromo-7-chloroquinoline;

4-bromo-6,8-dichloroquinoline;

4-bromo-7-trifluoromethylquinoline; and the like.

The 4-halo-quinolines can be prepared by known procedures from thecorresponding 4-hydroxy-quinolines, exemplary of which are:

4-hydroxyquinoline;

4-hydroxy-6-methoxyquinoline;

4-hydroxy-6-methylquinoline;

4-hydroxy-7-methoxyquinoline;

4-hydroxy-6,7-dimethoxyquinoline;

4-hydroxy-6,7-methylenedioxyquinoline;

4-hydroxy-7-trifluoromethylquinoline;

4-hydroxy-6,8-dimethoxyquinoline;

4-hydroxy-6-chloroquinoline;

4-hydroxy-7-chloroquinoline;

4-hydroxy-6,8-dichloroquinoline; and the like.

Yet another aspect of the invention is exemplified by Reaction SchemeIII.

Scheme III ##SPC6##

wherein R₁, R₂, R₃ and m are as previously described.

In Reaction Scheme III, the mixture of epimeric 5(R)-ethyl-(orvinyl)-4(S)-quinuclidine-2ξ-carboxylic acid alkyl esters of formulaVIII, enantiomers or racemates, is reacted with a 4-quinolyllithiumcompound of formula X to yield the corresponding mixture of epimeric4-[5(R)-ethyl(or vinyl)-4(S)-quinuclidin-2ξ-ylcarbonyl]quinolines offormula XI, enantiomers or racemates thereof. The 4-quinolyllithiumcompound of formula X is reacted in equimolar or greater than equimolarproportions with the compound of formula VIII. Preferably, two molarproportions of the quinolyllithium compound are utilized. The reactionis conveniently effected at room temperature or below room temperature,preferably in the range of about between 0° and about -70°C. Suitably,an inert solvent, for example, an ether, such as diethyl ether,tetrahydrofuran, dioxane and diglyme, or a hydrocarbon such as benzene,toluene, and the like, may be utilized. Further, the reaction may beconveniently carried out in the presence of complexing agents such as1,4-diazabicyclo[2.2.2] octane or tetramethylethylenediamine.

The conversion of the mixture of epimeric 4-[5(R)-ethyl(orvinyl)-4(S)-quinuclidin-2ξ-ylcarbonyl]quinolines of formula XI,enantiomers or racemates thereof, to α(S)-[5(R)-ethyl(orvinyl)-4(S)-quinuclidin-2(R)-yl]-4-quinolinemethanols of formula I,enantiomer or racemate thereof, and to α(R)-[5(R)-ethyl(orvinyl)-4(S)-quinuclidin-2(S)-yl]-4-quinolinemethanols of formula II,enantiomer or racemate, respectively, is carried out utilizing astereoselective reducing agent, for example, a dialkylaluminum hydride,such as diisobutylaluminum hydride or the like. The reduction issuitably carried out at room temperature; however, temperatures above orbelow room temperature may be employed. It is preferred to employ atemperature between 20°C. and 50°C. The reduction can be convenientlyconducted in the presence of an inert organic solvent, for example, ahydrocarbon such as benzene or toluene, or an ether such asdiethylether, tetrahydrofuran or the like.

The conversion of the compounds of formula XI, enantiomers or racematesthereof, to those of formulas I and II, enantiomers or racematesthereof, respectively, when R₂ is ethyl, can also be effected utilizinga hydrogenation catalyst such as nickel, palladium, ruthenium, copper orbarium chromite in the presence of a solvent, for example, an aqueous ornon-aqueous alkanol such as methanol or ethanol, or an ether such asdioxane. When R₂ is ethyl or vinyl, the conversion can be effectedutilizing a hydrogenation agent such as aluminum in ethanol, sodiumisopropoxide in toluene, sodium or potassium borohydride in methanol,ethanol, isopropanol or tetrahydrofuran, lithium aluminum hydride,aluminum hydride, chloroaluminum hydride, dichloroaluminum hydride,bromoaluminum hydride, dibromoaluminum hydride, lithiumtri-tert.-butoxyaluminum hydride in ether, tetrahydrofuran, dioxane orthe like.

The compounds of formulas I and II and their pharmaceutically acceptableacid addition salts possess antimalarial and antiarrhythmic propertiesand are therefore useful as antimalarial and antiarrhythmic agents.Their pharmacologically useful anti-arrhythmic activity is demonstratedin warm-blooded animals utilizing standard procedures, for example, thetest compound is administered to prepared mongrel dogs. The chest cavityof the experimental animal previously anesthetized using a combinationof sodium barbitol, 300 mg/kg. and pentobarbitol, 15 mg/kg., i.v., isopened up through the third right interspace under artificialrespiration and the pericardium is cut and sutured to the wall of thethorax so as to maintain the heart in a pericardial cradle throughoutthe course of the test procedure. Arterial pressure is monitored byinserting a polyethylene cannula into the aorta via the left carotidartery and is measured with an appropriate Statham pressure transducer.During the course of the experiment, electrical activity of the heart isviewed both on an oscilloscope and recorded on a Sanborn polyviso usingstandard ECG lead II. The heart is also observed visually. Theantiarrhythmic assay of the test drug is undertaken using a modificationof the method of Scherf and Chick, Circulation, 3, 764-769 (1951). Adripping of 1 percent solution of acetylcholine is applied to the sinusnode and the atrium is irritated by pinching with a pair of forceps.This procedure produces a continuous atrial arrhythmia which mostlyconsists of atrial fibrillation. Since hypokalemia produces asusceptibility to atrial fibrillation (Leveque, Arch. Int. Pharmacodyn,149, 297-307, 1964), 2 units/kg. of insulin is administered 30 minutesbefore the start of the acetylcholine drip. Once atrial fibrillation isestablished, there is a tenminute waiting period before the test drug isadministered. The test drugs are administered intravenously at the rateof 1 mg/kg/minute until normal sinus rhythm appears or until 30 mg/kg.of drug is administered.

The pharmacologically useful antimalarial activity of the aforementionedcompounds is demonstrated in warm-blooded animals using standardprocedures, for example, the test substance is administered to albinomice in variable amounts. Albino mice are inoculated with about 10million red cells infected with P. Berghei. Treatment is started on thefirst day after inoculation, and the drug is administered "per os"during 4 consecutive days. On the seventh day of infection, smears aremade, stained with giemsa and microscopically examined for P. Berghei.

When racemic 7'-methoxy-dihydrocinchonidine dihydrochloride and racemic7'-methoxy-dihydrocinchonine dihydrochloride are utilized as the testsubstance at dosages in the range of 125 mg/kg. to about 250 mg/kg., themicroscopical examination of the blood smears is free of P. Berghei(negative).

The compounds of formulas I and II, which include qunine and quinidineand their dihydro- analogs, have effects quantitatively similar, forexample, to those of quinine and quinidine of known therapeutic uses andproperties. Thus, the compounds prepared by the process of the inventiondemonstrate a pattern of activity associated with antimalarials andantiarrhythmics of known efficacy and safety.

The compounds of formulas I and II form pharmaceutically acceptable acidaddition salts and such salts are also within the scope of thisinvention. Thus, the aforementioned compounds form pharmaceuticallyacceptable addition salts with, for example, both pharmaceuticallyacceptable organic and inorganic acids, such as acetic acid, succinicacid, formic acid, methanesulfonic acid, p-toluene-sulfonic acid,hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid and thelike.

The products of the process of the invention can be incorporated intostandard pharmaceutical dosage forms, for example, they are useful fororal or parenteral application with the usual pharmaceutical adjuvantmaterials, e.g., organic or inorganic inert carrier materials such aswater, gelatin, lactose, starch, magnesium stearate, talc, vegetableoils, gums, polyalkyleneglycols, and the like. The pharmaceuticalpreparations can be employed in a solid form, e.g., as tablets, troches,suppositories, capsules, or in liquid form, e.g., as solutions,suspensions or emulsions. The pharmaceutical adjuvant materials caninclude preservatives, stabilizers, wetting or emulsifying agents, saltsto change the osmotic pressure or to act as buffers. They can alsocontain other therapeutically active materials.

The following examples further illustrate the invention. Alltemperatures are in degrees centigrade, unless otherwise mentioned.

EXAMPLE 1 Preparation of 6,7-methylenedioxy-4-quinolinol

A suspension of 50 g. of4-hydroxy-6,7-methylenedioxyquinoline-3-carboxylic acid in 500 ml. offreshly distilled quinoline was heated at 200° until the evolution ofgas ceased. The reaction mixture was cooled to room temperature, dilutedwith an equal amount of ether and kept cool overnight. The precipitatedbrown solid (51.4 g., m.p. 254°-267°) was collected by filtration anddissolved in refluxing ethanol. The insoluble material was removed andthe ethanol solution was reduced to one-third of its volume. Thesolution was diluted with an equal amount of ether. On cooling, 31.1 g.of 6,7-methylenedioxy-4-quinolinol separated, m.p. 280°-282°.Recrystallization (2x) from hot water yielded analytically pure6,7-methylenedioxy-4-quinolinol as a pale yellow solid, m.p. 288°-289°.

Analysis Calcd. for C₁₀ H₇ NO₃ (189.16): C, 63.49; H, 3.73; N, 7.41.Found: C, 63.58; H, 4.04; N, 7.34.

EXAMPLE 2 Preparation of 4-bromo-6,7-methylenedioxyquinoline

To a slurry of 10 g. of 6,7-methylenedioxy-4-quinolinol and 10 ml. ofphosphorus tribromide, preheated to 60°, was added 4 ml. of phosphorusoxybromide. The mixture was heated at 150°. After 1 hour, an additional4 ml. phosphorus oxybromide was added and heating was continued for 2hours with occasional stirring. The mixture was cooled to roomtemperature and carefully added to 1 l. of vigorously stirred crushedice. The precipitate was collected by filtration and, after washing withwater, was suspended in 100 ml. of water. The suspension was renderedalkaline by the addition of solid sodium bicarbonate. The precipitatewas collected by filtration, washed with water and extracted thoroughlywith chloroform. The organic extract was dried over sodium sulfate andevaporated to dryness to yield a nearly colorless solid which onsublimation at 100°-120° and 0.35 mmHg gave 8.3 g. of4-bromo-6,7-methylenedioxyquinoline, m.p. 147°-149°.

Analysis Calcd. for C₁₀ H₆ BrNO₂ (252.08): C, 47.65; H, 2.40; N, 5.56.Found: C, 47.57; H, 2.30; N, 5.42.

EXAMPLE 3 Preparation of 4-bromo-6,8-dichloroquinoline

A paste prepared from 33 g. of 6,8-dichloro-4-quinolinol and 50 ml. ofphosphorus tribromide was heated to 60°. After adding 20 ml. (56 g.) ofphosphorus oxybromide, the mixture was maintained at 150° for 3 hourswith occasional stirring. Then, the mixture was cooled and addedcarefully to 1.5 l. of vigorously stirred crushed ice. The aqueoussuspension was rendered alkaline by the addition of 12N sodiumhydroxide. The precipitate which formed was collected by filtration anddried in a vacuum oven. Sublimation of the dried material at 140° and0.3 mmHg yielded 35.7 g. of crystalline 4-bromo-6,8-dichloroquinoline,m.p. 163°-165°. Recrystallization from ether gave pure4-bromo-6,8-dichloroquinoline, m.p. 164°-166°.

Analysis Calcd. for C₉ H₄ BrCl₂ N (276.97): C, 39.03; H, 1.46; H, 5.05;Cl, 25.60. Found: C, 39.03; H, 1.32; N, 5.04; Cl, 25.61.

EXAMPLE 4 Preparation of1,1,1-trichloro-3-(3-ethyl-4-pyridinyl)propan-2(R)-ol and1,1,1-trichloro-3-(3-ethyl-4-pyridinyl)propan-2(S)-ol

To 106.6 g. of 1,1,1-trichloro-3-(3-ethyl-4-pyridinyl)propan-2-oldissolved in 1.2 l. of hot acetone was added a solution of 65.2 g. ofd-tartaric acid in 1 l. of acetone. Upon cooling, crystalline materialseparated (66.8 g.) which after fractional crystallization from acetone,yielded pure 1,1,1-trichloro-3-(3-ethyl-4-pyridinyl)propan-2(R)-old-tartrate, m.p. 176°-177.5°, [α]_(D) ²⁵ +30.7° (c 0.960, ethanol)

Analysis Calcd. for C₁₀ H₁₂ Cl₃ NO.C₄ H₆ O₆ (418.67): C, 40.16; H, 4.33;N, 3.35; Cl, 25.40. Found: C, 39.97; H, 4.18; N, 3.23; Cl, 25.59.

The tartrate salt was dissolved in water. The solution was renderedalkaline with a saturated aqueous solution of sodium carbonate andextracted four times with dichloromethane. The combined organic extractswere dried over sodium sulfate and evaporated to dryness under reducedpressure to give 1,1,1-trichloro-3-(3-ethyl-4-pyridinyl)propan-2(R)-ol,m.p. 132°-134°, [α]_(D) ²⁵ +45.1° (c 1.025, ethanol) afterrecrystallization from ether.

Analysis Calcd. for C₁₀ H₁₂ Cl₃ NO (268.58): C, 44.72; H, 4.51; N, 5.22;Cl, 39.60. Found: C, 44.99; H, 4.59; N, 4.96; Cl, 39.62.

The mother liquors obtained from the fractional crystallization werecombined and evaporated to dryness. The resulting residue was dissolvedin 4 l. of water. Insoluble material was removed by filtration, and thesolution was rendered alkaline with 6N sodium hydroxide. The resultingsolution was extracted three times with dichloromethane. The combinedorganic extract was washed three times with water, dried over sodiumsulfate and evaporated to dryness to give 57.2 g. of a brown solid. Asolution of this material in 800 ml. of acetone was combined with asolution of 31.8 g. of 1-tartaric acid in 700 ml. of acetone. Uponcooling, 54.9 g. of crystalline tartrate separated. Fractionalcrystallization of this material from acetone yielded pure1,1,1-trichloro-3-(3-ethyl-4-pyridinyl)propane-2(S)-ol 1-tartrate, m.p.177°-178°, [α]_(D) ²⁵ -30.3° (c 1.065, ethanol).

Analysis Calcd. for C₁₀ H₁₂ Cl₃ NO.C₄ H₆ O₆ (418.67): C, 40.16; H, 4.33;N, 3.35; Cl, 25.40. Found: C, 39.83; H, 4.63; N, 3.29; Cl, 25.32.

Pure 1,1,1-trichloro-3-(3-ethyl-4-pyridinyl)propan-2(S)-ol obtained from1,1,1-trichloro-3-(3-ethyl-4-pyridinyl)propan-2(S)-ol 1-tartrate, asdescribed above for the preparation of the other enantiomer had amelting point of 132°-134°, [α]_(D) ²⁵ -45.5° (c, 1.020, ethanol) afterrecrystallization from ether.

Analysis Calcd. for C₁₀ H₁₂ Cl₃ NO (268.58): C, 44.72; H, 4.51; N, 5.22;Cl, 39.60, Found: C, 45.05; H, 4.51; N, 5.04; Cl, 39.32.

EXAMPLE 5 Preparation of racemic1,1-dichloro-3-[3]-3(R)-ethyl-4(S)-piperidinyl] propan-2(S)-0lhydrochloride and racemic1,1-dichloro-3-[3(R)-ethyl-4(S)-piperidinyl]propan-2(R)-ol hydrochloride

To a solution containing 26.85 g. of racemic1,1,1-trichloro-3-(3-ethyl-4-pyridinyl)propan-2-ol in 400 ml. of 5percent aqueous hydrochloric acid was added 4 g. of platinum dioxide andthe mixture was hydrogenated at 60°C. and 67 atmospheres of pressure.After cooling to room temperature, the catalyst was removed byfiltration, and the resulting filtrate was evaporated in vacuo. Theresidue was crystallized from 70 ml. of absolute ethanol to give 10.5 g.(38 percent) of racemic1,1-dichloro-3-[3(R)-ethyl-4(S)-piperidinyl]propan-2(S)-olhydrochloride, having a melting point of 200°-205°, afterrecrystallization, m.p. 205°-209°.

Analysis Calcd. for C₁₀ H₂₀ Cl₃ NO (276.64): C, 43.42; H, 7.29; Cl,38.55; N, 5.06. Found: C, 43.69; H, 7.25; Cl, 38.35; N, 5.22.

Crystallization of the mother liquors from 30 ml. of acetone gave 9.5 g.(34.5 percent) of racemic1,1-dichloro-3-[3(R)-ethyl-4(S)-piperidinyl]propan-2(R)-olhydrochloride, having a melting point of 123°-129° after tworecrystallizations, m.p. 132°-134°.

Analysis Calcd. for C₁₀ H₂₀ Cl₃ NO (276.64) C, 43.42; H, 7.29; Cl,38.55; N, 5.06. Found: C, 43.38; H, 7.41; Cl, 38.37; N, 4.86.

EXAMPLE 6 Preparation of1,1-dichloro-3-[3(S)-ethyl-4(R)-piperidinyl]-propan-2(R)-olhydrochloride (A) and1,1-dichloro-3-[3(R)-ethyl-4(S)-piperidinyl]propan-2(R)-ol hydrochloride(B) ##SPC7##

A solution of 2.7 g. of1,1,1-trichloro-3-(3-ethyl-4-pyridinyl)propan-2(R)-ol (C) in 40 ml. of 5percent aqueous hydrochloric acid was hydrogenated over 0.4 g. ofplatinum oxide at 60°-90° and 65 atmospheres of pressure. After coolingto room temperature, the catalyst was removed by filtration, and theresulting filtrate was evaporated under reduced pressure. The residuewas crystalized from 40 ml. of ethanol to give 600 mg. of1,1-dichloro-3-[3(S)-ethyl-4(R)-piperidinyl]propan-2(R)-olhydrochloride, m.p. 232°-233°, [α]_(D) ²⁵ +29.63° (c 1.0953, methanol)after recrystallization from ethanol.

Analysis Calcd. for C₁₀ H₁₉ Cl₂ NO.HCl (276.65): C, 43.42; H, 7.28; N,5.06. Found: C, 43.11; H, 7.32; N, 4.98.

The mother liquors were concentrated and crystallization of the residuefrom acetone gave 557 mg. of1,1-dichloro-3-[3(R)-ethyl-4(S)-piperidinyl]propan-2(R)-olhydrochloride, m.p. 168°-170°, [α]_(D) ²⁵ +25.25° (c 1.0140, methanol),after recrystallization from acetone.

Analysis Calcd. for C₁₀ H₁₉ Cl₂ NO.HCl (276.65): C, 43.42; H, 7.78; N,5.06. Found: C, 43.55; H, 7.47; N, 5.00.

EXAMPLE 7 Preparation of 1,1-dichloro-3-[3(R)-ethyl-4(S)-piperidinyl]propan-2(S)-ol hydrochloride (D) and1,1-dichloro-3-[3(S)-ethyl-4(R)-piperidinyl]propan-2(S)-ol hydrochloride(E) ##SPC8##

A solution of 2.7 g. of1,1,1-trichloro-3-(3-ethyl-4-pyridinyl)propan-2(S)-ol (F) in 40 ml. of 5percent aqueous hydrochloric acid was hydrogenated over 0.4 g. ofplatinum oxide at 60° and 65 atmospheres of pressure. After cooling toroom temperature, the catalyst was removed by filtration, and thefiltrate was concentrated under reduced pressure. The residue wascrystallized from 20 ml. of ethanol to give 600 mg. of1,1-dichloro-3-[3(R)-ethyl-4(S)-piperidinyl]propan-2(S)-olhydrochloride, m.p. 227°-229°. Several recrystallizations from ethanolyielded pure 1,1-dichloro-3-[3(R)-ethyl-4(S)-piperidinyl]-propan-2(S)-olhydrochloride, m.p. 232-233°, [α]_(D) ²⁵ -28.3° (c 1.0237, methanol).

Analysis Calcd. for C₁₀ H₁₉ Cl₂ NO.HCl (276.65): C, 43.42; H, 7.28; N,5.06. Found: C, 43.58; H, 7.32; N, 5.08.

The free base obtained from1,1-dichloro-3-[3(R)-ethyl-4(S)-piperidinyl]propan-2(S)-ol hydrochlorideon treatment with aqueous potassium carbonate and extraction withdichloromethane, was combined with ethanolic hydrogen bromide to give1,1-dichloro-3-[3(R)-ethyl-4(S)-piperidinyl]propan-2(S)-ol hydrobromide,m.p. 223°-224°, [α]_(D) ²⁵ -24.77° (c, 0.9486, methanol), after severalrecrystallizations from ethanol.

Analysis Calcd. for C₁₀ H₁₉ Cl₂ NO.HBr (321.11):

C, 37.41; H, 6.28; N, 4.36. Found: C, 37.71; H, 6.44; N, 4.46.

The mother liquors obtained from the crystallization of1,1-dichloro-3-[3(R)-ethyl-4(S)-piperidinyl]propan-2(S)-ol hydrochloridewere combined and concentrated under reduced pressure. The residue wastriturated with acetone and the crystalline material was recrystallizedfrom acetone to give 729 mg. of1,1-dichloro-3-[3(S)-ethyl-4(R)-piperidinyl]propan-2(S)-olhydrochloride. Recrystallization from acetone yielded1,1-dichloro-3-[3(S)-ethyl-4(R)-piperidinyl]propan-2(S)-olhydrochloride, m.p. 169.5°-171.5°, [α]_(D) ²⁵ -25.15° (c 0.9306,methanol).

Analysis Calcd. for C₁₀ H₁₉ Cl₂ NO.HCl (276.65): C, 43.42; H, 7.28; N,5.06. Found: C, 43.69; H, 7.49; N, 5.34.

EXAMPLE 8 Preparation of1,1-dichloro-3-[3(R)-vinyl-4(S)-piperidinyl]-propan-2(S)-olhydrochloride and1,1-dichloro-3-[3(R)-vinyl-4(S)-piperidinyl]propan-2(R)-ol hydrochloride

To a solution containing 3.07 ml. of methylene chloride in 60 ml. ofanhydrous tetrahydrofuran cooled to -70°, there was added over a periodof 1 hour 44 mmoles of n-butyllithium in 28 ml. of hexane under anatmosphere of dry nitrogen. Stirring of the mixture at the sametemperature was continued for 20 minutes and then followed by thedropwise addition of 5.19 g. (20 mmoles) of2-[1-benzoyl-3(R)-vinyl-4(S)-piperidinyl]acetaldehyde in 30 ml. ofanhydrous tetrahydrofuran. After 30 minutes, the reaction was quenchedby the addition of 30 ml. of water. The mixture was allowed to warm upto room temperature and was subsequently extracted three times withether. The combined ether extracts were washed with water, dried oversodium sulfate and evaporated to dryness. The residue was dissolved in80 ml. of 3N hydrochloric acid. The acidic solution was washed withether and neutralized with 3N sodium hydroxide. The solution was washedwith ether, rendered alkaline by the addition of 3N sodium hydroxide andextracted with ether. The ether extract was washed with water, driedover sodium sulfate and evaporated to dryness. The residue (3.8 g.) wasdissolved in ethanol and treated with an excess of ethanolic hydrogenchloride. The solvent was evaporated under reduced pressure and theresulting solid residue was crystallized from ethanol to give 2.0 g. ofa mixture of epimeric1,1-dichloro-3-[3(R)-vinyl-4(S)-piperidinyl]propan-2ξ-ol hydrochlorides.Fractional crystallization from ethanol followed by recrystallization ofthe combined fractions from ethanol gave1,1-dichloro-3-[3(R)-vinyl-4(S)-piperidinyl]propan-2(S)-olhydrochloride, m.p. 225-225.5°, [α]_(D) ²⁵ -13.3° (c 1.02, methanol).

Analysis Calcd. for C₁₀ H₁₇ Cl₂ NO.HCl (274.62): C, 43.74; H, 6.61; N,5.10. Found: C, 43.71; H, 6.53; N, 4.85.

The mother liquors were combined and evaporated to dryness.Recrystallization of the residue from acetone gave1,1-dichloro-3-[3(R)-vinyl-4(S)-piperidinyl]propan-2(R)-olhydrochloride, m.p. 165°-167°, [α]_(D) ²⁵ + 30.7° (c 1.00, methanol).

Analysis Calcd. for C₁₀ H₁₇ Cl₂ NO.HCl (274.62): C, 43.74; H, 6.61; N,5.10. Found: C, 44.01; H, 6.86; N, 4.78.

EXAMPLE 9 Preparation of1,1-dichloro-3-[3(R)-ethyl-4(S)-piperidinyl]propan-2(S)-ol hydrochlorideand 1,1-dichloro-3-[3(R)-ethyl-4(S)-piperidinyl]propan-2(R)-olhydrochloride

To a solution containing 6.35 ml. of methylene chloride in 120 ml. ofanhydrous tetrahydrofuran cooled to -70° there was added over a periodof 2 hours 90 mmoles of n-butyllithium in 55.5 ml. of hexane under anatmosphere of dry nitrogen. The mixture was stirred at the sametemperature for 30 minutes and then followed by the dropwise addition of5.8 g. (22.4 mmoles) of2-[1-benzoyl-3(R)-ethyl-4(S)-piperidinyl]acetaldehyde in 60 ml. ofanhydrous tetrahydrofuran. After 30 minutes, the reaction was quenchedby the addition of 30 ml. of water. The mixture was allowed to warm upto room temperature and was subsequently extracted three times withether. The combined ether extracts were extracted with 300 ml. of 10percent aqueous hydrochloric acid. The acidic solution was washed twicewith each 100 ml. of ether and evaporated to complete dryness. Theresidue was dissolved in the minimal amount of hot ethanol. Uponstanding, there was obtained 1.1 g. of1,1-dichloro-3-[3(R)-ethyl-4(S)-piperidinyl]propan-2 (S)-olhydrochloride, mp 239-240°, [α]²⁵ D -28.6° (c 1.005, methanol), afterrecrystallization from ethanol.

The mother liquors were combined and evaporated to dryness.Recrystallization of the residue from acetone gave1,1-dichloro-3-[3(R)-ethyl-4(S)-piperidinyl]propan-2(R)-olhydrochloride, mp 172°-173°, [α]²⁵ D +25.2° (c 1.00, methanol).

EXAMPLE 10 Preparation of epimeric, racemic4,5-erythro-5-ethylquinuclidine-2ξ-carboxaldehydes

a. To a solution containing 2.77 g. of racemic1,1-dichloro-3-[3(R)-ethyl-4(S)-piperidinyl]propan-2(S)-ol HCl in 20 ml.of methanol was added a solution containing 1.68 g. of potassiumhydroxide in 15.8 ml. of methanol. The mixture was stirred at roomtemperature for 55 hours. The precipitate formed in the reaction wasremoved by filtration, and the filtrate was evaporated to dryness. Theresidue was treated with 200 ml. of ether, and the insoluble part wasremoved by filtration. The filtrate was evaporated to dryness to yieldand oily mixture of epimeric, racemic4,5-erythro-5-ethylquinuclidine-2ξ-carboxaldehydes.

b. The methanolic solution containing crude aldehyde prepared as abovefrom 5.45 g. of racemic1,1-dichloro-3-[3(R)-ethyl-4(S)-piperidinyl]propan-2(S)-ol hydrochloridewas evaporated to dryness under reduced pressure at a temperature below30°. The residue was dissolved in 300 ml. of ether, insoluble materialwas removed by filtration, and evaporation of the filtrate gave 4.12 g.of oily residue. A solution of the residue in 100 ml. of ether was addedto a solution containing 2.5 g. of sodium bisulfite in 8 ml. of water.The solvents were removed under reduced pressure, and the residue wasdissolved in 10 ml. of water. Addition of ethanol followed by theaddition of ether precipitated 3.4 g. of solid addition product. Thisproduct was added to 50 ml. of a saturated aqueous sodium carbonate andheated at 40°. After all material had dissolved, the solution was keptat 40° for another 5 minutes. The mixture was cooled and extracted threetimes with ether. The combined ether extracts were dried over potassiumcarbonate and evaporated to dryness under reduced pressure to give 950mg. of liquid aldehyde. Distillation in a short path distillationapparatus at 60°-85° (oil bath temperature) under a pressure of 0.4mmHg. gave 648 mg. of analytically pure mixture of epimeric, racemic,4,5-erythro-5-ethylquinuclidine-2ξ-carboxaldehydes.

Analysis Calcd. for C₁₀ H₁₇ NO (167.24): C, 71.81; H, 10.25; N, 8.38.Found: C, 71.91; H, 10.02; N, 8.58.

c. A solution containing 1.39 g. of racemic1,1-dichloro-3-[3(R)ethyl-4(S)-piperidinyl]propan-2(R)-ol HCl in 25 ml.of water was combined with 150 ml. of benzene. The stirred mixture wascooled in an ice bath and 8.56 ml. of a 1.75N potassium hydroxidesolution was added slowly. Stirring at room temperature was continuedunder an atmosphere of nitrogen for 20 hours. The aqueous layer wasseparated and extracted with benzene. The combined organic layer wasdried over sodium sulfate and evaporated under reduced pressure atapproximately 30°. The residue was distilled in a short pathdistillation apparatus at 60°-85° (oil bath temperature) and 0.3 mmHg.to give 600 mg. (72 percent) of a mixture of epimeric, racemic4,5-erythro-5-ethylquinuclidine-2ξ-carboxaldehydes.

d. To a solution of 400 mg. of racemic, epimeric cis1,1-dichloro-3-(3-ethyl-4-piperidinyl)propan-2ξ-ols in 50 ml. ofmethanol was added 5 g. of Amberlite anion exchange resin IRA-401 (OH).The mixture was stirred at room temperature overnight. The resin wasremoved by filtration. The filtrate was concentrated to near drynessunder reduced pressure and the residue was treated with benzene. Thebenzene solution was dried over MgSO₄ and evaporated to dryness underreduced pressure to give epimeric, racemic4,5-erythro-5-ethylquinuclidine-2ξ-carboxaldehydes.

EXAMPLE 11 Preparation of epimeric5(R)-ethyl-4(S)-quinuclidine-2ξ-carboxaldehydes

a. A solution containing 1.14 g. of1,1-dichloro-3-[3(R)-ethyl-4(S)-piperidinyl]propan-2(S)-ol hydrochloridein 20 ml. of water was combined with 450 ml. of benzene. The stirredmixture was cooled in an ice bath and 7.4 ml. of a 1.68N potassiumhydroxide solution was added slowly. Stirring at room temperature wascontinued under an atmosphere of nitrogen for 20 hours. The aqueouslayer was separated and extracted with benzene. The combined organiclayer was dried over sodium sulfate and evaporated under reducedpressure at 30°. The residue on evaporative bulb-to-bulb distillation at80° and 0.1 mmHg yielded 283 mg. of liquid epimeric5(R)-ethyl-4(S)-quinuclidine-2ξ-carboxaldehydes, [α]²⁵ D +102.61 (c1.1383, methanol).

Analysis Calcd. for C₁₀ H₁₇ NO (167.24): C, 71,81; H, 10.25; N, 8.38.Found: C, 71.75; H, 9.97; N, 8.44.

b. Utilizing the procedure above, a mixture of 1.94 g. of1,1-dichloro-3-[3(R)-ethyl-4(S)-piperidinyl]propan-2(S)-ol hydrochlorideand 1,1-dichloro-3-[3(R)-ethyl-4(S)-piperidinyl]propan-2(R)-olhydrochloride gave after evaporative bulb-to-bulb distillation at 80°and 0.3 mmHg 538 mg. of epimeric5(R)-ethyl-4(S)-quinuclidine-2ξ-carboxaldehydes.

EXAMPLE 12 Preparation of epimeric5(S)-ethyl-4(R)-quinuclidine-2ξ-carboxaldehydes

A solution containing 1.34 g. of1,1-dichloro-3-[3(S)-ethyl-4(R)-piperidinyl]propan-2(S)-ol hydrochloridein 10 ml. of water was combined with 150 ml. of benzene. The stirredmixture was cooled in an ice-bath and 8.7 ml. of a 1.68N potassiumhydroxide solution was added slowly. Stirring at room temperature wascontinued under an atmosphere of nitrogen for 20 hours. The aqueouslayer was separated and extracted with benzene. The combined organiclayer was dried over sodium sulfate and evaporated under reducedpressure at 30°. The residue on evaporative bulb-to-bulb distillation at90° and 0.1 mmHg yielded 500 mg. of liquid epimeric5(S)-ethyl-4(R)-quinuclidine-2ξ-carboxaldehydes, [α]²⁵ D -85.56° (c1.0682, methanol).

Analysis Calcd. for C₁₀ H₁₇ NO (167.24): C, 71.81; H, 10.25; N, 8.38.Found: C, 71.55; H, 10.29; N, 8.65.

EXAMPLE 13 Preparation of epimeric5(R)-vinyl-4(S)-quinuclidine-2ξ-carboxaldehydes

A solution containing 2.36 g. of a mixture of1,1-dichloro-3-[3(R)-vinyl-4(S)-piperidinyl]propan-2(S)-ol hydrochlorideand 1,1-dichloro-3-[3(R)-vinyl-4(S)-piperidinyl]propan-2(R)-olhydrochloride in 35 ml. of water was combined with 850 ml. of benzene.The stirred mixture was cooled in an ice bath and 15.4 ml. of 1.68Npotassium hydroxide solution was added slowly under a nitrogenatmosphere. Stirring at room temperature was continued for 16 hours. Theaqueous layer was separated and extracted with benzene. The combinedorganic layers were washed with water, dried over sodium suflate andevaporated under reduced pressure at 30°. The residue on evaporativebulb-to-bulb distillation at 60° and 0.05 mmHg. yielded 767 mg. ofliquid epimeric 5(R)-vinyl-4(S)-quinuclidine-2ξ-carboxaldehydes, [α]²⁵ D+154.85° (c 0.8957, chloroform).

EXAMPLE 14 Preparation of epimeric, racemic4,5-erythro-5-ethylquinuclidine-2ξ-carboxylic acid ethyl esters

a. To a solution containing 8.3 g. of racemic1,1-dichloro-3-[3(R)-ethyl-4(S)-piperidinyl]propan-2(S)-ol hydrochloridein 600 ml. of methanol cooled to 0° was added dropwise with stirring asolution of 5.04 g. of potassium hydroxide in 23.4 ml. of methanol.After completed addition, the temperature of the mixture was allowed torise to room temperature and stirring was continued overnight. Insolublematerial was removed by filtration, and the solution was added to amixture of 11.7 g. of silver nitrate and 4.8 g. of sodium hydroxide in200 ml. of water. The reaction mixture, after stirring for 3 hours atroom temperature, was filtered through Celite-Filter Aid and thefiltrate was saturated with hydrogen sulfide. The precipitate wasremoved by filtration through Celite-Filter Aid and the filtrate wasevaporated to dryness. The residue was treated with 500 ml. of ethanol,and the mixture was refluxed for 3 hours. After filtering throughCelite-Filter Aid, the filtrate containing a mixture of epimeric,racemic 4,5-erythro-5-ethylquinuclidine-2ξ -carboxylic acids wassaturated with anhydrous hydrogen chloride and refluxed overnight. Theprecipitate was removed by filtration, and the filtrate was evaporatedto dryness. The yellow oil obtained was treated with 300 ml. of asaturated aqueous solution of sodium carbonate and extracted five timeswith ether. The combined ether extract was dried over sodium sulfate andevaporated to dryness under reduced pressure. The residue was distilledin a short path distillation apparatus at 70°-75°C. (oil bathtemperature) under a pressure of 0.3 mmHg. to give 3.81 g. (60 percent)of a liquid mixture of epimeric, racemic4,5-erythro-5-ethylquinuclidine-2ξ-carboxylic acid ethyl esters.

Gas chromatography on a column of 4 percent PEG 4000 MS on Gaschrom Z at150° showed the material to consist of two isomers in a 1:1 ratio withretention times of t_(o) = 8.5 min. and t_(o) = 9.4 min. A separation ofthe two isomers was achieved by preparative gas chromatography. In themass spectrum, both isomers showed a low resolution molecular ion peakat m/e 211 and a base peak at m/e 138.

b. To a solution of 5 ml. of methylene chloride in 70 ml. of anhydroustetrahydrofuran cooled to -70° was added during 1 hour 35 ml. of a 1.66Msolution of n-butyllithium in hexane under an atmosphere of drynitrogen. The mixture was stirred at the same temperature for 20minutes, which was followed by the dropwise addition of 6.8 g. ofracemic 2-[1-benzoyl-3(R)-ethyl-4(S)-piperidinyl]acetaldehyde in 30 ml.of anhydrous tetrahydrofuran. After 30 minutes, the reaction wasquenched by the addition of 30 ml. of water. The mixture was allowed towarm up to room temperature and was subsequently extracted three timeswith ether. The combined ether extracts were washed with water, driedover sodium sulfate and evaporated to dryness. The product (4 g.), amixture of racemic, epimeric1,1-dichloro-3-[3(R)-ethyl-4(S)-piperidinyl]propan-2ξ-ols, was dissolvedin 400 ml. of methanol. A solution of 1.8 g. of potassium hydroxide in45 ml. of methanol was added and stirring was continued for 50 hours atroom temperature. Then, the solution containing a mixture of racemic,epimeric 4,5-erythro-5-ethylquinuclidine-2ξ-carboxaldehydes was combinedwith a mixture of 2.56 g. of sodium hydroxide and 5.44 g. of silvernitrate in 60 ml. of water. The reaction mixture, after being stirredfor 3 hours at room temperature, was filtered through Celite-Filter Aid,and the filtrate was evaporated to dryness. Complete dryness was ensuredby the addition of an ethanol-benzene solvent mixture to the residuefollowed by removal of the solvents under reduced pressure. Theprocedure was repeated several times. The residue was extractedrepeatedly with hot ethanol. The combined extracts were evaporated todryness and the residue containing a mixture of epimeric, racemic4,5-erythro-5-ethylquinuclidine-2ξ-carboxylic acids, was esterified with4 percent ethanolic hydrogen chloride to give, after usual work-up anddistillation under reduced pressure, 1.8 g. of a mixture of epimeric,racemic 4,5-erythro- 5-ethylquinuclidine-2ξ-carboxylic acid ethylesters.

EXAMPLE 15 Preparation of epimeric, racemic4,5-erythro-5-ethylquinuclidine-2ξ-carboxylic acid methyl esters

A mixture of epimeric, racemic4,5-erythro-5-ethylquinuclidine-2ξ-carboxylic acids, obtained from 5.53g. of racemic 1,1-dichloro-3-[3(R)-ethyl-4(S)-piperidinyl]propan-2(S)-olHCl by the reaction sequence outlined previously in Example 10 (a), wasdissolved in 350 ml. of methanol. Concentrated sulfuric acid (5 ml.) wasadded, and the mixture was refluxed overnight. After the addition ofanother 2 ml. of concentrated sulfuric acid, refluxing was continued foranother 15 hours. The volume was reduced to approximately 30 ml. byevaporation under reduced pressure. The resulting residue was renderedalkaline with a saturated aqueous solution of sodium carbonate anddiluted with dichloromethane. The insoluble material was removed byfiltration and dissolved in the minimal amount of water. The aqueousphase was extracted three times with dichloromethane and the extractswere combined with the filtrate. The combined organic layer was driedover potassium carbonate and evaporated under reduced pressure. Theresidue, on distillation, gave 2.33 g. (59 percent) of a liquid mixtureof epimeric, racemic 4,5-erythro-5-ethylquinuclidine-2ξ-carboxylic acidmethyl esters, b.p. 84°-85°/0.35 mmHg.

EXAMPLE 16 Preparation of epimeric5(R)-ethyl-4(S)-quinuclidine-2ξ-carboxylic acid ethyl esters

To a solution containing 3.2 g. of a mixture of1,1-dichloro-3-[3(R)-ethyl-4(S)-piperidinyl]propan-2(S)-ol hydrochlorideand 1,1-dichloro-3 [ 3(R)-ethyl-4(S)-piperidinyl]propan-2(R)-olhydrochloride in 350 ml. of methanol cooled to 0° was added dropwisewith stirring a solution of 1.95 g. of potassium hydroxide in 21.7 ml.of methanol. Stirring was continued at room temperature overnight. Theinsoluble material was removed by filtration, and the solution was addedto a mixture of 3.96 g. of silver nitrate and 1.85 g. of sodiumhydroxide in 35 ml. of water. The reaction mixture, after stirring for 4hours at room temperature, was filtered through Celite-Filter Aid andthe filtrate was evaporated to dryness. The residue was extracted with200 ml. of boiling ethanol. The extract containing a mixture of epimeric5(R)-ethyl-4(S)-quinuclidine-2ξ-carboxylic acids was evaporated tocomplete dryness. The residue was dissolved in 4 percent ethanolichydrogen chloride and the solution was refluxed overnight. Thisprocedure was repeated once more. After removal of the precipitate byfiltration, the filtrate was evaporated to dryness. The residue wasrendered alkaline with a saturated aqueous solution of potassiumcarbonate and extracted three times with ether. The combined etherextracts were dried over potassium carbonate and evaporated to drynessunder reduced pressure. Evaporative bulb-to-bulb distillation at 95°-97°and 0.05 mmHg of the crude product yielded 1 g. of liquid epimeric5(R)-ethyl-4(S)-quinuclidine-2ξ-carboxylic acid ethyl ester, [α]²⁵ D+77.32° (c 1.0489, methanol).

Analysis Calcd. for C₁₂ H₂₁ NO₂ (211.30): C, 68.21; H, 10.02; N, 6.63.Found: C, 68.47; H, 10.25; N, 6.74.

EXAMPLE 17 Preparation of epimeric, racemic4,5-erythro-5-ethylquinuclidine-2ξ-carboxylic acids hydrochlorides

A solution containing 2.15 g. of a mixture of epimeric, racemiic4,5-erythro-5-ethylquinuclidine-2ξ-carboxylic acid ethyl esters in 100ml. of 1N hydrochloric acid was left standing at room temperature for 10days. The solution was washed with ether and evaporated to dryness underreduced pressure. Complete dryness was ensured by repeatedly addingtoluene to the residue and removing the solvent under reduced pressure.The residue was crystallized from ethanol-ether to give 429 mg. of amixture of epimeric, racemic4,5-erythro-5-ethylquinuclidine-2ξ-carboxylic acids hydrochlorides, m.p.239°-242° .

Analysis Calcd. for C₁₀ H₁₇ NO₂.HCl (219.72): C, 54.67; H, 8.26; N,6.38. Found: C, 54.80; H 8.35; N, 6.24.

The concentrated mother liquor was treated again with 1N hydrochloricacid and yielded an additional 353 mg. of a mixture of epimeric, racemic4,5-erythro-5-ethylquinuclidine-2ξ-carboxylic acid hydrochlorides.

EXAMPLE 18 Preparation of epimeric5(R)-vinyl-4(S)-quinuclidine-2ξ-carboxylic acid ethyl esters

Utilizing the conditions described in Example 8, 6.48 g. of2-[1-benzoyl-3(R)-vinyl-4(S)-piperidinyl]acetaldehyde was reacted withdichloromethyllithium prepared from 3.7 ml. of methylene chloride and 55mmoles of n-butyllithium. The resulting product (4.1 g.), a mixture ofepimeric 1,1-dichloro-3-[3(R)-vinyl-4(S)-piperidinyl]propan-2ξ-ols, wasdissolved in 400 ml. of methanol. A solution containing 1.9 g. ofpotassium hydroxide in 20 ml. of methanol was added and stirring wascontinued for 50 hours at room temperature. The solution containing amixture of epimeric 5(R)-vinyl-4(S)-quinuclidine-2ξ-carboxaldehydes wascombined with a mixture of 2.56 g. of sodium hydroxide and 5.78 g. ofsilver nitrate in 40 ml. of water. The resulting reaction mixture, afterbeing stirred for 3 hours at room temperature, was filtered throughCelite-Filter Aid, and the filtrate was evaporated to dryness. Completedryness was ensured by the addition of an ethanol-benzene solventmixture to the residue followed by removal of the solvents under reducedpressure. The procedure was repeated several times. The residue wasextracted repeatedly with hot ethanol. The combined extract wasevaporated to dryness and the residue containing a mixture of epimeric5(R)-vinyl-4(S)-quinuclidine-2ξ-carboxylic acids was partially dissolvedin 100 ml. of 8 percent ethanolic hydrogen chloride. The reactionmixture was stirred at room temperature for 3 days and then evaporatedto dryness. The residue was treated again with 100 ml. of 5 percentethanolic hydrogen chloride for 15 hours. The solvent was removed underreduced pressure, and the residue was combined with 100 ml. of asaturated aqueous solution of potassium carbonate. The mixture wasextracted three times with ether. The combined ether extracts were driedover sodium sulfate and evaporated to dryness under reduced pressure.The residue was distilled in a short path distillation apparatus at 77°(oil bath temperature) under a pressure of 0.15 mmHg. to give 1.88 g.(36 percent) of liquid epimeric5(R)-vinyl-4(S)-quinuclidine-2ξ-carboxylic acid ethyl esters; [α]_(D) ²⁵+82.2° (c 1.1, 95% ethanol).

EXAMPLE 19 Preparation of epimeric5(R)-vinyl-4(S)-quinuclidine-2ξ-carboxylic acids

A suspension of 310 mg. of epimeric5(R)-vinyl-4(S)-quinuclidine-2ξ-carboxylic acid ethyl esters in 10 ml.of water was left standing at room temperature. After 10 days, a clearsolution was obtained. The water was evaporated under reduced pressure,and the residue was sublimed at 165° under a pressure of 0.15 mmHg. togive 210 mg. of very hygroscopic crystalline epimeric5(R)-vinyl-4(S)-quinuclidine-2ξ-carboxylic acids; [α]_(D) ²⁵ +78.4° (c0.72, CHCl₃), [α]_(D) ²⁵ +93.2° (c 0.87, 1N NaOH) measured immediatelyand [α]_(D) ²⁵ +80.8° (c 0.87, 1N NaOH) after heating the solution at100° for 16 hours.

EXAMPLE 20 Preparation of racemic dihydroquininone and racemicdihydroquinidinone

a. To a solution containing 488 mg. of 4-bromo-6-methoxyquinoline in 20ml. of anhydrous ether was added under nitrogen at -50° 0.45 ml. of a2.25M solution of butyllithium in hexane. The suspension containing6-methoxy-4-quinolyllithium was stirred at this temperature for another15 minutes and then a solution of 433 mg. of a mixture of epimeric,racemic 4,5-erythro-5-ethyl-quinuclidine-2ξ-carboxylic acid ethyl estersin 20 ml. of anhydrous ether was added over a period of 20 minutes.After stirring at -50° for another 1.5 hours, the mixture was warmed toroom temperature and hydrolyzed by the addition of water. The aqueouslayer was separated and extracted three times with ether. The combinedorganic solution was dried over sodium sulfate and evaporated todryness. The crude product was chromatographed on silica gel preparativeplates with ether as solvent. The plates were run three times. Elutionwith methanol gave 100 mg. of a yellow oil which on further treatmentgave 50 mg. of a crystalline mixture of racemic dihydroquininone andracemic dihydroquinidinone, m.p. 86°-90°.

b. To 5 ml. of anhydrous ether was added 0.67 ml. of 1.66M solution ofbutyllithium in hexane. The resulting solution was cooled to -70° andwith stirring and under a nitrogen atmosphere, 119 mg. of4-bromo-6-methoxyquinoline dissolved in 5 ml. of ether was added. Thesuspension containing 6-methoxy-4-quinolyllithium was combined with 56mg. of 1,4-diazabicyclo[2.2.2]octane dissolved in 5 ml. of anhydrousether and the mixture was stirred at -70° for 2 hours. Thereafter, asolution of 126 mg. of a mixture of epimeric, racemic4,5-erythro-5-ethylquinuclidine-2ξ-carboxylic acid ethyl esters in 5 ml.of anhydrous ether was added. After stirring at -70° for 30 minutes, themixture was quenched with water and allowed to warm up to roomtemperature. The aqueous layer was separated and extracted with ether.The combined organic solution was dried over sodium sulfate andevaporated to dryness to give 184 mg. of an oil containing racemicdihydroquininone and racemic dihydroquinidinone.

Utilizing the procedure described above, there can be obtained:

a. from 7-chloro-4-quinolyllithium, a mixture of racemic7'-chlorodihydrocinchonidinone and racemic 7'-chlorodihydrocinchoninone,m.p. 124°-127°;

b. from 6-methyl-4-quinolyllithium, a mixture of racemic6'-methyldihydrocinchonidinone and racemic 6'-methyldihydrocinchoninone,m.p. 105°-108°;

c. from 6-chloro-4-quinolyllithium, a mixture of racemic6'-chlorodihydrocinchonidinone and racemic 6'-chlorodihydrocinchoninone,m.p. 104°-107°;

d. from 7-methoxy-4-quinolyllithium, a mixture of racemic7'-methoxydihydrocinchonidinone and racemic7'-methoxydihydrocinchoninone, m.p. 111°-117°; and the like.

EXAMPLE 21 Preparation of racemic dihydroquinine and racemicdihydroquinidine from a mixture of racemic dihydroquininone and racemicdihydroquinidinone

To a solution of 5.06 g. of a crystalline mixture of racemicdihydroquininone and dihydroquinidinone in 500 ml. of dry benzene wasadded dropwise 12.5 ml. of a 25 percent solution of diisobutylaluminumhydride in toluene with stirring under an atmosphere of dry nitrogen.After approximately 30 minutes, the reaction was quenched by theaddition of 2 ml. of methanol-water (1:1). The precipitated alumina wasseparated by filtration and washed thoroughly with methanol. The residueof the methanol washings (3.87 g.) was crystallized from acetoneyielding 3.14 g. (61 percent) of racemic dihydroquinine monohydrate inthree crops. The residue of the benzene solution (1.54 g.) wascrystallized from a concentrated solution in ethanol yielding 579 mg.(11 percent) of racemic dihydroquinidine in four crops. Afterpurification on preparative tlc (chloroform-triethylamine-methanol,85:10:5) more d,1-dihydroquinidine and d,1-dihydroquinine could becrystallized from ethanol and acetone, respectively.

Utilizing the procedure described above:

a. from a mixture of racemic 7'-chlorodihydrocinchonidinone and racemic7'-chlorodihydrocinchoninone, there can be obtained racemic7'-chlorodihydrocinchonidine, m.p. 192°-193°, and racemic7°-chlorodihydrocinchonine, m.p. 251°-253° dec.;

b. from a mixture of racemic 7'-methoxydihydrocinchonidinone and racemic7'-methoxydihydrocinchoninone, there can be obtained racemic7'-methoxydihydrocinchonidine, m.p. 160°, and racemic7'-methoxydihydrocinchonine, m.p. 217°-219°;

c. from a mixture of racemic 6'-methyldihydrocinchonidinone and racemic6'-methyldihydrocinchoninone, there can be obtained, racemic6'-methyldihydrocinchonidine, m.p. 216-218°, and racemic6'-methyldihydrocinchonine, m.p. 153.5° - 155°;

d. from a mixture of racemic 6'-chlorodihydrocinchonidinone and racemic6'-chlorodihydrocinchoninone, there can be obtained racemic6'-chlorodihydrocinchonidine, m.p. 100°-102°, and racemic6'-chlorodihydrocinchonine, m.p. 172.5° - 173.5°.

EXAMPLE 22 Preparation of Quinine and Quinidine

To 100 ml. of anhydrous ether there was added 14.5 ml. of a 1.45Msolution of n-butyllithium in hexane. The resulting solution was cooledto -70° and with stirring a solution of 4.76 g. of4-bromo-6-methoxyquinoline in 100 ml. of anhydrous ether was added underan atmosphere of dry nitrogen. The yellow suspension of6-methoxy-4-quinolyllithium in ether which immediately formed wasstirred at -70° for 2 hours. A solution of 2.1 g. of epimeric5(R-vinyl-4(S)-quinuclidine-2ξ-carboxylic acid ethyl esters in 100 ml.of anhydrous ether was added, and after 30 mins., the reaction wasquenched by the addition of water and allowed to warm up to roomtemperature. The ethereal solution was washed with water, dried oversodium sulfate and evaporated to dryness under reduced pressure to yield5.08 g. of an oil which contained a mixture of quininone andquinidinone. To a cooled solution of 4.74 g. of the above material in100 ml. of anhydrous benzene, there was slowly added 13 ml. of a 25percent solution of diisobutylaluminum hydride in toluene under anatmosphere of dry nitrogen. The reaction was quenched after 1 hour bythe addition of 20 ml. of water-methanol (1:1) with vigorous stirring.The precipitate which formed was collected by filtration and washedthoroughly with methanol. The filtrate was dried over anhydrous sodiumsulfate and evaporated to dryness. A solution of the residue inchloroform was washed successively with 1N sodium hydroxide and water,dried over anhydrous sodium sulfate and evaporated to dryness. Theproduct (4.1 g.) was chromatographed on 150 g. of neutral alumina(Woelm, activity I) with ethyl acetate-benzene (1:1) (500 ml.), ethylacetate (800 ml.) and methanol (400 ml.) as eluent. Evaporation of themethanol fraction gave 2.5 g. of product which was chromatographed onsilica gel preparative plates (20 × 20 × 0.2 cm.) withchloroform-triethylamine-methanol (85:10:5) as the solvent mixture.Elution of the lowest of three major bands with chloroform-methanol(1:1) gave 289 mg. of a yellow oil which was dissolved in ethanol, andon treatment with 44 mg. of d-tartaric acid in ethanol yielded thecrystalline, neutral tartrate of quinine, m.p. 214°-215°, [α]_(D).sup.25 -149° (c, 0.985, MeOH). The compound showed ir-spectrum and tlc R_(f)-value identical with those of an authentic sample. The melting pointwas not depressed on admixture with an authentic specimen. Elution ofthe middle band with methanol-chloroform (1:1) gave 311 mg. ofquinidine, which after recrystallization from ethanol and drying at 80°under reduced pressure for 15 hours showed m.p. 170°-172°, [α]_(D) ²² +261° (c, 0.995, ethanol). The ir-spectrum and the tlc R_(f) -value wereidentical with those of authentic material. No depression of the meltingpoint was observed on admixture with an authentic sample. The upperband, upon elution with methanol-chloroform (1:1) yielded 95 mg. of oilyresidue which was identical with an authentic mixture of epiquinine andepi-quinidine.

Utilizing the reaction conditions described above:

a. from 7-chloro-4-quinolyllithium, there can be obtained,7'-chlorocinchonidine, m.p. 177-179°, and 7'-chlorocinchonine, m.p.245°-246°;

b. from 6,8-dichloro-4-quinolyllithium, there can be obtained,6',8'-dichlorocinchonidine, m.p. 105°-108°, and 6',8'-dichlorocinchoninedihydrochloride monohydrate, m.p. 250° dec.;

c. from 6-chloro-4-quinolyllithium, there can be obtained,6'-chlorocinchonidine, m.p. 193°-194°, and 6'-chlorocinchonine, m.p.154°-155°;

d. from 4-quinolyllithium, there can be obtained, cinchonidine andcinchonine.

EXAMPLE 23 Preparation of Quinine and Quinidine

To 30 ml. of anhydrous ether was added 2.74 ml. of a 1.62M solution ofbutyllithium in hexane. The resulting solution was cooled to -70°. Withstirring under a nitrogen atmosphere, a solution of 1.08 g. of4-bromo-6-methoxyquinoline in 30 ml. of anhydrous tetrahydrofuran wasadded. After stirring the mixture containing 6-methoxy-4-quinolyllithiumfor 30 minutes at -70°, a solution of 748 mg. of freshly distilled5(R)-vinyl-4(S)-quinuclidine-2ξ-carboxaldehyde in 15 ml. of anhydrousether was added over a period of 30 minutes. After the addition wascompleted, stirring was continued for two hours at 70°. The reactionmixture then was hydrolyzed by the addition of water and extractedseveral times with ether. The organic extract was washed with water,dried over anhydrous sodium sulfate and evaporated to dryness. Theresidue was chromatographed on Merck F-254 silica gel preparative plateswith chloroform-triethylamine-methanol (85:10:5) as the solvent mixture.Elution of three separate bands and purification of the eluates yielded215 mg. of quinidine [mp 172-173°; [α]_(D) ²⁵ +265.6° (c 1.07, 95percent ethanol)], 220 mg. of the neutral d-tartrate of quinine [mp211-212°; [α]_(D) ²⁵ -159.5° (c 1.00, methanol)], and 330 mg. of amixture of epi-quinine and epi-quinidine.

EXAMPLE 24 Preparation of racemic 6',8'-dichlorodihydrocinchonidinedihydrochloride and racemic 6',8'-dichlorodihydrocinchoninedihydrochloride

a. To 500 ml. of anhydrous ether was added 38 ml. of 1.45M solution ofbutyllithium in hexane. The resulting solution was cooled to -68° andwith stirring and under a nitrogen atmosphere 13.8 g. of4-bromo-6,8-dichloroquinoline dissolved in 175 ml. of anhydroustetrahydrofuran was added over a period of 30 minutes. Subsequently, asolution of 5.3 g. of a mixture of epimeric, racemic4,5-erythro-5-ethylquinuclidine-2ξ-carboxylic acid ethyl esters in 250ml. of anhydrous ether was added to the 6,8-dichloro-4-quinolyllithium,thus prepared, and stirring was continued for one hour at -70°. Thereaction was then quenched by the addition of water and allowed to warmup to room temperature. The organic solution was washed with water,dried over sodium sulfate and evaporated to dryness under reducedpressure to yield 19.0 g. of an oily residue containing a mixture ofracemic 6',8'-dichlorodihydrocinchonidinone and racemic6',8'-dichlorodihydrocinchoninone. This material was dissolved in 250ml. of anhydrous benzene and cooled. To the cooled solution there wasadded over a period of 15 minutes 17 ml. of a 25% solution ofdiisobutylaluminum hydride in toluene under an atmosphere of drynitrogen. The reaction mixture was stirred for one hour at roomtemperature and then quenched by the addition of 20 ml. ofwater-methanol (1:1). The precipitate was collected by filtration andwashed thoroughly with methanol. A solution of the residue in chloroformwas washed with 1N sodium hydroxide and water. The organic solutionswere combined, dried over sodium sulfate and evaporated to dryness underreduced pressure. The resulting product (14.1 g.) was chromatographed on500 g. of neutral alumina (Woelm, activity I) with ethyl acetate (1.8l.) followed by methanol (2.2 l.) as the eluent. Evaporation of themethanol fractions yielded 5.27 g. of product which together with 6.9 g.of material obtained previously was chromatographed on 700 g. of silicagel (Silica Gel 0.05- 0.2 mm.; i.d. of column = 55 mm.). Fractions of250 ml. each were collected. After 25 fractions withchloroform-triethylamine (97:3) as the liquid phase, the composition ofthe eluent was changed to 96:4. Fractions 29- 40 were combined,evaporated to dryness and the residue was dissolved in dichloromethane.The organic solution was washed twice with water, dried over sodiumsulfate and evaporated to dryness under reduced pressure.Crystallization of the residue (1.79 g.) from a mixture ofbenzene-hexane (1:2) gave 1.3 g. of crystalline, racemic 6',8'-dichlorodihydrocinchonine. Recrystallization from benzene-hexane (1:1)and drying of the sample at 80° under reduced pressure to constantweight yielded racemic 6',8'-dichlorodihydrocinchonine, containing 1/3mole of benzene: m.p. 172°-173°.

Analysis Calcd. for C₁₉ H₂₂ Cl₂ N₂ O . 1/3 C₆ H₆ (391.35): C, 64.45; H,6.18; N, 7.15; Cl, 18.12. Found: C, 64.63; H, 6.42; N, 7.28; Cl, 18.46.

The dihydrochloride salt of 6',8'-dichlorodihydrocinchonine was preparedby dissolving 1.05 g. of the free base in a minimal amount of ethanolichydrogen chloride. Upon addition of ether to the solution, 1.0 g. ofcrystalline racemic 6',8'-dichlorodihydrocinchonine dihydrochlorideprecipitated, m.p. 210°-212°. Upon two recrystallizations fromethanol-ether the melting point was 214°-215° (dried for 100 minutes at80° under reduced pressure).

Analysis Calcd. for C₁₉ H₂₂ Cl₂ N₂ O.2HCl (438.22): C, 52.07; H, 5.52;N, 6.39; Cl, 32.36. Found: C, 52.14; H, 5.56; N, 6.42; Cl, 31.90.

Fractions 42- 57 were combined and evaporated to dryness. The residuewas dissolved in dichloromethane. The solution was washed twice withwater, dried over sodium sulfate and evaporated to dryness under reducedpressure. The residue (1.56 g.) was dissolved in the minimal amount ofethanolic hydrogen chloride and upon addition of ether to the solution1.15 g. of crystalline racemic 6',8'-dichlorodihydrocinchonidinedihydrochloride was precipitated. Recrystallization from methanol-etheryielded analytically pure racemic 6',8'-dichlorodihydrocinchonidinedihydrochloride, m.p. 226°-227°.

Analysis Calcd. for C₁₉ H₂₂ Cl₂ N₂ O.2HCl (438.22): C, 52.07; H, 5.52;N, 6.39; Cl, 32.36. Found: C, 52.04; H, 5.63; N, 6.29; Cl, 32.17.

b. To 500 ml. of anhydrous ether was added 38 ml. of 1.45M solution ofbutyllithium in hexane. The resulting solution was cooled to -70° andwith stirring and under a nitrogen atmosphere, 13.8 g. of4-bromo-6,8-dichloroquinoline dissolved in 200 ml. of anhydroustetrahydrofuran was added. Stirring of the solution of6,8-dichloro-4-quinolyllithium was continued at -70° for another 10minutes, followed by the addition of 5.6 g. of anhydroustetramethylethylenediamine dissolved in 250 -quinuclidine-of anhydrousether. After additional stirring for 15 minutes, there was added 5.8 g.of a mixture of epimeric, racemic4,5-erythro-5-ethylquinuclidine-2ξ-carboxylic acid ethyl ester dissolvedin 250 ml. of anhydrous ether. The mixture was stirred at -70° for onehour, then quenched by the addition of water and allowed to warm up toroom temperature. The organic solution was washed with water, dried oversodium sulfate and evaporated to dryness under reduced pressure to yield17.5 g. of an oily residue containing a mixture of racemic6',8'-dichlorodihydrocinchonidinone and racemic6',8'-dichlorodihydrocinchoninone. Subsequent conversion to racemic6',8'-dichlorodihydrocinchonidine dihydrochloride and6',8'-dichlorodihydrocinchonine was carried out as described in (a)above.

Utilizing the reaction conditions described above:

a. from 6,7-dimethoxy-4-quinolyllithium there can be obtained, racemic6,7-dimethoxydihydrocinchonidine dihydrochloride, m.p. 208°-210° dec.,and racemic 6',7'-dimethoxydihydrocinchonine dihydrochloride, m.p.221°-225°;

b. from 6,7-methylenedioxy-4-quinolyllithium, there can be obtainedracemic 6',7'-methylenedioxydihydrocinchonidine, m.p. 232°-233°, andracemic 6',7'-methylenedioxydihydrocinchonine, m.p. 234°-235°.

EXAMPLE 25 Preparation of racemic dihydroquinine and racemicdihydroquinidine

To 30 ml. of anhydrous ether was added 2.22 ml. of a 2.25M solution ofbutyllithium in hexane. The resulting solution was cooled to -68°C. andwith stirring under a nitrogen atmosphere 1.19 g. of4-bromo-6-methoxyquinoline was added. Immediately, a yellow suspensionof 6-methoxy-4-quinolyllithium was formed. To this suspension was addedwithin 5 minutes a solution of 1.42 g. of the crude mixture of epimeric,racemic 4,5-erythro-5-ethylquinuclidine-2ξ-carboxaldehydes in 30 ml. ofanhydrous ether. After the addition was completed, stirring wascontinued for one hour at -65°C. The reaction mixture was then pouredinto an ice-water slurry and extracted with dichloromethane. Thedichloromethane extract was washed with water, dried over anhydroussodium sulfate and evaporated to dryness. The residue thus obtained wasdissolved in dichloromethane and the solution was extracted twice with2N hydrochloric acid. The acidic extract was washed with dichloromethaneand then made alkaline by the addition of 6N aqueous sodium hydroxide.The free bases thus liberated were extracted into dichloromethane. Theextract was washed with water, dried over anhydrous sodium sulfate andevaporated to dryness to give crude oily product. The crude product waschromatographed on Merck F-254 silica gel preparative plates withchloroform-triethylamine-methanol (85:10:5) mixture. Elution of twoseparated bands gave racemic dihydroquinidine, m.p. 153°-155° andracemic dihydroquinine, m.p. 171°-172°.

EXAMPLE 26 Preparation of racemic6',7'-methylenedioxydihydrocinchonidine and racemic6',7'-methylenedioxydihydrocinchonine

To 250 ml. of anhydrous ether was added 19.3 ml. of a 1.45M solution ofn-butyllithium in hexane. The resulting solution was cooled to -68°.Thereafter, there was added 6.55 g. of4-bromo-6,7-methylenedioxyquinoline dissolved in 200 ml. of anhydroustetrahydrofuran over a period of 30 minutes with stirring and under anitrogen atmosphere to afford 6,7-methylenedioxy-4-quinolyllithium.Stirring of the mixture was continued at the same temperature for 30minutes followed by the addition of a solution of 2.15 g. of a mixtureof epimeric, racemic 4,5-erythro-5-ethylquinuclidine-2ξ-carboxaldehydesin 250 ml. of ether over a period of one hour. The reaction mixture wasstirred at -70° under a nitrogen atmosphere overnight. After quenchingwith water, the mixture was allowed to warm to room temperature andsubsequently was concentrated under reduced pressure. The residue wasdissolved in ether. The ethereal solution was washed with water, driedover sodium sulfate and evaporated to dryness to give 6.54 g. of an oil.Chromatography on neutral alumina (Woelm, activity I) with ethyl acetateyielded 2.97 g. of a yellow solid. Subsequent elution with methanolyielded 3.37 g. of a brown oil. This was chromatographed on silica gelpreparative plates (20 × 20 × 0.2 cm) with ethyl acetate-triethylamine(97:3) as the solvent mixture. The plates were developed three times.Elution of the lowest major band with methanolchloroform andcrystallization of the eluate (510 mg.) from acetone gave racemic6',7'-methylenedioxy-dihydrocinchonidine, m.p. 232°-233°. Elution of thenext higher band with methanolchloroform and crystallization of theeluate (597 mg.) from acetone gave racemic6',7'-methylenedioxydihydrocinchonine, m.p. 234°-235°.

Analysis Calcd. for C₂₀ H₂₄ N₂ O₃ (340.41): C, 70.56; H, 7.11; N, 8.23.Found: C, 70.25; H, 7.29; N, 8.05.

Utilizing the procedure described above:

a. from 6-methyl-4-quinolyllithium, there can be obtained racemic6'-methyldihydrocinchonidine, m.p. 216°-218° and racemic6'-methyldihydrocinchonine, m.p. 153.5° - 155°;

b. from 6-chloro-4-quinolyllithium, there can be obtained racemic6'-chlorodihydrocinchonidine, m.p. 100°-102°, and racemic6'-chlorodihydrocinchonine, m.p. 172.5° - 173.5°;

c. from 6,7-dimethoxy-4-quinolyllithium, there can be obtained racemic6',7'-dimethoxydihydrocinchonidine dihydrochloride, m.p. 208°-210° dec.,and racemic 6',7'-dimethoxydihydrocinchonine dihydrochloride, m.p.221°-225°;

d. from 7-methoxy-4-quinolyllithium, there can be obtained racemic7'-methoxydihydrocinchonidine, m.p. 160°, and racemic7'-methoxydihydrocinchonine, m.p. 217°-219°;

e. from 6,8-dichloro-4-quinolyllithium, there can be obtained racemic6',8'-dichlorodihydrocinchonidine dihydrochloride, m.p. 226°-227°, andracemic 6',8'-dichlorodihydrocinchonine dihydrochloride, m.p. 214°-215°.

EXAMPLE 27 Preparation of racemic 7'-chlorodihydrocinchonidine andracemic 7'-chlorodihydrocinchonine

To a solution of 5.2 ml. of 1.62M butyllithium (in hexane) in 40 ml. ofanhydrous ether and 10 ml. of anhydrous tetrahydrofuran was added at-70° under an atmosphere of nitrogen, 2.1 g. of4-bromo-7-chloroquinoline dissolved in 30 ml. of anhydroustetrahydrofuran. Stirring of the mixture containing7-chloro-4-quinolyllithium was continued at the same temperature for 30minutes followed by the addition of a solution of 1.4 g. of a mixture ofepimeric, racemic 4,5-erythro-5-quinuclidine-12ξ-carboxaldehydes in 20ml. of anhydrous ether. The reaction mixture was stirred at -70° for 2hours. After quenching with water, the mixture was allowed to warm toroom temperature. The aqueous layer was separated and extracted twicewith ether. The combined organic extract was dried over sodium sulfateand evaporated to dryness under reduced pressure. The residue waschromatographed on 300 g. of silica gel (Merck 70-325) withchloroform-triethylamine as the liquid phase to afford racemic7'-chlorodihydrocinchonidine, mp 188°-190° after recrystallization fromacetone (mixture mp with an authentic sample 188°-190°), and racemic7'-chlorodihydrocinchonine, mp 251°-252° after recrystallization fromethanol (mixture mp with an authentic sample 251°-252°).

EXAMPLE 28 Preparation of Dihydroquinine and Dihydroquinidine

To 20 ml. of anhydrous ether was added 1.98 ml. of a 1.62M solution ofbutyllithium in hexane. The resulting solution was cooled to -70° andwith stirring under a nitrogen atmosphere a solution of 760 mg. of4-bromo-6-methoxyquinoline in 20 ml. of anhydrous tetrahydrofuran wasadded. After stirring the mixture containing 6-methoxy-4-quinolyllithiumfor 30 minutes at -70°, a solution of 538 mg. of freshly distilled5(R)-ethyl-4(S)-quinuclidine-2ξ-carboxaldehyde in 10 ml. of anhydrousether was added during 15 minutes. After completion of the addition,stirring was continued for two hours at -70°. The reaction mixture thenwas hydrolyzed by the addition of water, allowed to warm up to roomtemperature and diluted with an equal volume of ether. The aqueous layerwas separated and extracted three times with 15 ml. of ether each. Thecombined organic extract was dried over sodium sulfate and evaporated todryness. The residue was chromatographed on silica gel plates (MerckF-254) with chloroform-triethylamine-methanol (85:10:5) as the solventmixture. Elution of the lowest of the major bands withchloroform-methanol (1:1) gave 138 mg. of dihydroquinine, mp 169°-170°after recrystallization from chloroform-ether, [α]²⁵ D - 144.5° (c0.935, 95 percent ethanol). The melting point was not depressed onadmixture with a natural sample. Elution of the next higher band withchloroform-methanol (1:1) gave 210 mg. of an oil which was dissolved inethanol. Upon standing, crystalline dihydroquinidine separated, mp169°-170° (mixed mp with natural material 169°-170°) [α]²⁵ D + 222° (c0.970, ethanol). From the third band elution with chloroform-methanol(1:1) yielded 87 mg. of a mixture of dihydroepiquinine anddihydroepiquinidine. The mixture was dissolved in benzene and treatedwith 48 mg. of dibenzoyl-d-tartaric acid in benzene-acetone. Thesolvents were evaporated to dryness and the residue afterrecrystallization from benzene yielded the neutral dibenzoyl-d-tartrateof dihydroepiquinidine, mp 168°-170°, [α]²⁵ D -13.7° [c 0.970,ethanol-chloroform (4:1)].

EXAMPLE 29

                  Tablet Formulation                                              ______________________________________                                                              Per Tablet                                              Racemic 7'-methoxydihydrocinchonine                                                                   25.00 mg.                                             Dicalcium Phosphate Dihydrate,                                                 unmilled               175.00 mg.                                            Corn Starch             24.00 mg.                                             Magnesium Stearate      1.00 mg.                                              Total Weight            225.00 mg.                                            ______________________________________                                    

Procedure

25 Parts of racemic 7'-methoxy-dihydrocinchonine and 24 parts of cornstarch were mixed together and passed through a No. 00 screen in Model"J" Fitzmill with hammers forward. This premix was then mixed with 175parts of dicalcium phosphate and one-half part of magnesium stearate,passed through a No. 1A screen in Model J Fitzmill with knives forward,and slugged. The slugs were passed through a No. 2A plate in a Model "D"Fitzmill at slow speed with knives forward, and the remaining magnesiumstearate was added. The mixture was mixed and compressed.

EXAMPLE 30

                  Capsule Formulation                                             ______________________________________                                                             Per Capsule                                              Racemic 7'-methoxydihydrocinchonine                                                                   50 mg.                                                Corn Starch, U.S.P.    150 mg.                                                Talc, U.S.P.            10 mg.                                                7Total Weight          210 mg.                                                ______________________________________                                    

Procedure

Fifty parts of racemic 7'-methoxy-dihydrocinchonine were mixed with 150parts of corn starch in a suitable mixer. The mixture was furtherblended by passing through a Fitzpatrick Comminuting Machine with a No.1A screen with knives forward. The blended powder was returned to themixer and 10 parts of talc were added and blended thoroughly. Themixture was filled into No. 4 hard shell gelatin capsules on a ParkeDavis capsulating machine.

EXAMPLE 31

                  Suppository Formulation                                         ______________________________________                                                              Per 1.3 Gm.                                                                   Suppository                                             Racemic 7'-methoxydihydrocinchonidine                                                                 0.025 gm.                                             Hydrogenated Coconut Oil                                                                              1.230 gm.                                             Carnauba Wax            0.045 gm.                                             ______________________________________                                    

Procedure

123 Parts of hydrogenated coconut oil (Wecobee M- E. F. Drew Co., NewYork, New York) and 4.5 parts of carnauba wax were melted in a suitablesize glass lined container (stainless steel may also be used), mixedwell and cooled to 45°C. 2.5 Parts of racemic7'-methoxydihydrocinchonidine, which had been reduced to a fine powderwith no lumps, was added and stirred until completely and uniformlydispersed. The mixture was poured into suppository molds to yieldsuppositories having an individual weight of 1.3 gms. The suppositorieswere cooled and removed from molds and individually wrapped in wax paperfor packaging.

We claim:
 1. A racemic epimer of the formula ##SPC9##wherein R₃ is loweralkyl.
 2. An epimer in accordance with claim 1, racemic4,5-erythro-5-ethylquinuclidine-2 ξ-carboxylic acid ethyl ester.
 3. Anepimer in accordance with claim 1, racemic4,5-erythro-5-ethylquinuclidine-2 ξ-carboxylic acid methyl ester.
 4. Aracemic epimer of the formula ##SPC10##
 5. A racemic epimer inaccordance with claim 4, 4,5-erythro-5-ethylquinuclidine-2 ξ-carboxylicacid.